The problems of drug abuse continue to plague society. Studies are proposed for continuing the investigation of alterations in brain biochemistry by drugs which are currently abused. We have found that toxic doses of methamphetamine (10-15 mg/kg) depress tyrosine hydroxylase activity in the rat nigro-striatal system while chlorpromazine and haloperidol prevent this response. Models to explain these effects have been proposed which invoke GABA inhibitory neurons in the substantia nigra. The feasibility of these models will be tested by determining the effect of methamphetamine on GABA levels in the substantia nigra of rats and by monitoring the influence of altered GABA levels on nigral and striatal dopamine and acetylcholine turnover. Changes in the kinetic characteristics of tyrosine hydroxylase will also be measured. Because of concurrent multiple drug abuse, the influence of delta 9-tetrahydrocannabinol on the methamphetamine-induced changes in nigral and striatal tyrosine hydroxylase activity will be studied. Since the mesolimbic dopaminergic system is under consideration as a potential site of action for the antipsychotic drugs, the effects of large doses of methamphetamine, which simulate psychosis in humans, will be examined in this system and the possible antagonitic effects of chlorpromazine, haloperiod, and clozapine will be examined. Although the proposed experiments are most relevant to drug abuse and to the regulation of tyrosine hydroxylase in brain dopaminergic systems, it is anticipated that this investigation will also provide information pertinent to a better understanding of schizophrenia and parkinsonism. Tyrosine hydroxylase and acetylcholine will be measured by accepted standard radiometric methods. GABA will be transaminated and the NADPH generated will be measured fluorometrically. Dopamine will be measured by an enzymatic radiometric technique.